Eicosanoid
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Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from
EPA & DGLA.
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon
essential fatty acids, (EFAs). They exert complex control over many bodily systems, mainly in
inflammation or immunity, and as messengers in the central nervous system. The networks of
controls that depend upon eicosanoids are among the most complex in the human body.
Eicosanoids derive from either omega-3 (ω-3) or omega-6 (ω-6) EFAs. The ω-6 eicosanoids are
generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a
person's diet will affect the body's eicosanoid-controlled functions, with effects on
cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such
as aspirin and other NSAIDs act by downregulating eicosanoid synthesis.
There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and
the leukotrienes. For each, there are two or three separate series, derived either from an ω-3 or ω6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6
fats.[1][2][3][4]
Contents






1 Nomenclature
2 Biosynthesis
o 2.1 Peroxidation and reactive oxygen species
o 2.2 Prostanoid pathways
o 2.3 Leukotriene pathways
3 Function and pharmacology
o 3.1 The ω-3 and ω-6 series
 3.1.1 Mechanisms of ω-3 action
o 3.2 Role in inflammation
o 3.3 Action of prostanoids
o 3.4 Action of leukotrienes
4 History
5 References
6 External links
[edit] Nomenclature
See related detail at Essential Fatty Acid Interactions—Nomenclature
"Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term[5] for
oxygenated derivatives of three different 20-carbon essential fatty acids:



Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds;
Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds;
Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bonds.
Current usage limits the term to the leukotrienes (LT) and three types of prostanoids—
prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition
used in this article. However, several other classes can technically be termed eicosanoid,
including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epi-lipoxins,
epoxyeicosatrienoic acids (EETs) and endocannabinoids. LTs and prostanoids are sometimes
termed 'classic eicosanoids'[6][7][8] in contrast to the 'novel', 'eicosanoid-like' or 'nonclassic
eicosanoids'.[9][10][11][12]
A particular eicosanoid is denoted by a four-character abbreviation, composed of:



Its two letter abbreviation (above),[13]
One A-B-C sequence-letter;[14] and
A subscript, indicating the number of double bonds.
Examples are:

The EPA-derived prostanoids have three double bonds, (e.g. PGG3, PGH3, PGI3, TXA3)
while its leukotrienes have five, (LTB5).
 The AA-derived prostanoids have two double bonds, (e.g. PGG2, PGH2, PGI2, TXA2)
while its leukotrienes have four, (LTB4).
Furthermore, stereochemistry may differ among the pathways, indicated by Greek letters,
e.g. for (PGF2α).
[edit] Biosynthesis
Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:


Cyclooxygenase, or COX, generates the prostanoids.
Lipoxygenase, or LOX, in several forms. 5-lipoxygenase (5-LO) generates the
leukotrienes.
Eicosanoids are not stored within cells, but are synthesized as required. They derive from the
fatty acids that make up the cell membrane and nuclear membrane.
Eicosanoid biosynthesis begins when cell is activated by mechanical trauma, cytokines,
growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring
cell; the pathways are complex.) This triggers the release of a phospholipase at the cell
membrane. The phospholipase travels to the nuclear membrane. There, the phospholipase
catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C).
This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining
step for eicosanoid formation.
The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic
phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of
eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain
AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the
lysophospholipid that becomes platelet-activating factor.[15]
[edit] Peroxidation and reactive oxygen species
Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways
table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2).
Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation
proceeds with high stereospecificity.
The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There
are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the
phospholipases are tightly controlled—there are at least eight proteins activated to coordinate
generation of leukotrienes. Several of these exist in multiple isoforms.[4]
Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the
initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can
form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage;
murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.[16][17] The
oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage.
The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide
hydrolases and carrier proteins) belong to families whose functions are largely involved with
cellular detoxification. This suggests that eicosanoid signaling may have evolved from the
detoxification of ROS.
The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus.
PGs and LTs may signal or regulate DNA-transcription there; LTB4 is ligand for PPARα.[2]
(See diagram at PPAR).
Structures of Selected Eicosanoids
Prostaglandin E1. The 5Thromboxane A2.
Leukotriene B4. Note the 3
member ring is characteristic
Oxygens
conjugated double bonds.
of the class.
have moved into the ring.
Prostacyclin I2. The second ring
distinguishes it from the prostaglandins.
Leukotriene E4, an example of a
cysteinyl leukotriene.
[edit] Prostanoid pathways
See Prostanoid#Biosynthesis.
Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to
prostanoids by a two-step process. First, two molecules of O2 are added as two peroxide
linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain.
This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of
the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more
detail of these steps at Cyclooxygenase).
All three classes of prostanoids originate from PGH. All have distinctive rings in the
center of the molecule. They differ in their structures. The PGH compounds (parents to
all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example
in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a
single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another
oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one
oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes
involved, in diagrams at Prostanoid.)
Several drugs lower inflammation by blocking prostanoid synthesis; see detail at
Cyclooxygenase, Aspirin and NSAID.
[edit] Leukotriene pathways
See Leukotriene#Biosynthesis.
The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to
convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which
spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme LTA
synthase acts on 5-HPETE to convert it into leukotriene A4 (LTA4), which may be
converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast
cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate
glutathione with LTA4 to make LTC4, which is transported outside the cell, where a
glutamic acid moiety is removed from it to make LTD4. The leukotriene LTD4 is then
cleaved by dipeptidases to make LTE4. The leukotrienes LTC4, LTD4 and LTE4 all
contain cysteine and are collectively known as the cysteinyl leukotrienes.
[edit] Function and pharmacology
Metabolic actions of selected prostanoids and leukotrienes†[15]
Stimulation of platelet
PGD2 Promotion of sleep
TXA2
aggregation; vasoconstriction
Smooth muscle contraction;
PGE2 inducing pain, heat, fever;
15d-PGJ2
Adipocyte differentiation
bronchoconstriction
PGF2α Uterine contraction
LTB4
Leukocyte chemotaxis
Inhibition of platelet aggregation;
Anaphylaxis; bronchial smooth
PGI2
Cysteinyl-LTs
vasodilation; embryo implantation
muscle contraction.
†
Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity
Eicosanoids exert complex control over many bodily systems, mainly in inflammation or
immunity, and as messengers in the central nervous system. They are found in most
living things. In humans, eicosanoids are local hormones that are released by most cells,
act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators),
and then are rapidly inactivated.
Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants
inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against
thromboxane and some leukotrienes.[18] Most eicosanoid receptors are members of the G
protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid
receptors.
Receptors: There are specific receptors for all eicosanoids (see also: eicosanoid
receptors)
Leukotrienes:



CysLT1 (Cysteinyl leukotriene
receptor type 1)
CysLT2 (Cysteinyl leukotriene
receptor type 2)
BLT1 (Leukotriene B4 receptor)
Prostanoids:





PGD2: DP-(PGD2)
PGE2:
o EP1-(PGE2)
o EP2-(PGE2)
o EP3-(PGE2)
o EP4-(PGE2)
PGF2α: FP-(PGF2α)
PGI2 (prostacyclin): IP-(PGI2)
TXA2 (thromboxane): TP-(TXA2)
[edit] The ω-3 and ω-6 series
Main article: Essential fatty acid interactions
“
The reduction in AA-derived eicosanoids and the diminished activity
of the alternative products generated from ω-3 fatty acids serve as the
foundation for explaining some of the beneficial effects of greater ω-3
intake.
”
—Kevin Fritsche, Fatty Acids as Modulators of the Immune Response [19]
Arachidonic acid (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more
than twenty different eicosanoid-mediated signaling paths controlling a wide array of
cellular functions, especially those regulating inflammation, immunity and the central
nervous system.[3]
In the inflammatory response, two other groups of dietary essential fatty acids form
cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3)
provides the most important competing cascade. DGLA (20:3 ω-6) provides a third, less
prominent cascade. These two parallel cascades soften the inflammatory effects of AA
and its products. Low dietary intake of these less-inflammatory essential fatty acids,
especially the ω-3s, has been linked to several inflammation-related diseases, and
perhaps some mental illnesses.
The U.S. National Institutes of Health and the National Library of Medicine state that
there is 'A' level evidence that increased dietary ω-3 improves outcomes in
hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension.
There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in
primary prevention of cardiovascular disease, rheumatoid arthritis and protection from
ciclosporin toxicity in organ transplant patients. They also note more preliminary
evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.[20]
Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune
response through three other molecular mechanisms. They (a) alter membrane
composition and function, including the composition of lipid rafts; (b) change cytokine
biosynthesis and (c) directly activate gene transcription.[19] Of these, the action on
eicosanoids is the best explored.
[edit] Mechanisms of ω-3 action
EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At
each step, the ω-3 and ω-6 cascades compete for the enzymes.
The eicosanoids from AA generally promote inflammation. Those from EPA and from
GLA (via DGLA) are generally less inflammatory, or inactive, or even antiinflammatory. The figure shows the ω-3 and -6 synthesis chains, along with the major
eicosanoids from AA, EPA and DGLA.
Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three
ways, along the eicosanoid pathways:



Displacement—Dietary ω-3 decreases tissue concentrations of AA, so there is less to
form ω-6 eicosanoids.
Competitive inhibition—DGLA and EPA compete with AA for access to the
cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in
tissues lowers the output of AA's eicosanoids.
Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA
derived counterparts.
[edit] Role in inflammation
Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth),
dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with
each of these signs.
Redness—An insect's sting will trigger the classic inflammatory response. Short acting
vasoconstrictors — TXA2—are released quickly after the injury. The site may
momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and
LTB4. The blood vessels engorge and the injury reddens.
Swelling—LTB4 makes the blood vessels more permeable. Plasma leaks out into the
connective tissues, and they swell. The process also loses pro-inflammatory cytokines.
Pain—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing
pain neurons.
Heat—PGE2 is also a potent pyretic agent. Aspirin and NSAIDS—drugs that block the
COX pathways and stop prostanoid synthesis—limit fever or the heat of localized
inflammation.
Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists/antagonists used as
medicines
Medicine
Type
Medical condition or use
Alprostadil
PGE1
Erectile dysfunction, maintaining a
patent ductus arteriosus in the fetus
Beraprost
PGI1 analog
Pulmonary hypertension, avoiding
reperfusion injury
Bimatoprost
PG analog
Glaucoma, ocular hypertension
Carboprost
PG analog
Labor induction, abortifacient
in early pregnancy
Dinoprostone
PGE2
Labor induction
Iloprost
PGI2 analog
Pulmonary arterial hypertension
Latanoprost
PG analog
Glaucoma, ocular hypertension
Misoprostol
PGE1 analog
Stomach ulcers, labor induction,
abortifacient
Montelukast
LT receptor
antagonist
Asthma, seasonal allergies
Travoprost
PG analog
Glaucoma, ocular hypertension
Treprostinil
PGI analog
Pulmonary hypertension
U46619
Longer lived
TX analog
Research only
Zafirlukast
LT receptor
antagonist
Asthma
[edit] Action of prostanoids
Main articles: Prostaglandin, Prostacyclin and Thromboxane
Prostanoids mediate local symptoms of inflammation: vasoconstriction or
vasodilation, coagulation, pain and fever. Inhibition of cyclooxygenase, specifically
the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal antiinflammatory drugs), such as aspirin. COX-2 is responsible for pain and
inflammation, while COX-1 is responsible for platelet clotting actions.
Prostanoids activate the PPARγ members of the steroid/thyroid family of nuclear
hormone receptors, directly influencing gene transcription.[21]
[edit] Action of leukotrienes
Main article: Leukotriene
Leukotrienes play an important role in inflammation. There is a neuroendocrine role
for LTC4 in luteinizing hormone secretion.[22] LTB4 causes adhesion and chemotaxis
of leukocytes and stimulates aggregation, enzyme release, and generation of
superoxide in neutrophils.[23] Blocking leukotriene receptors can play a role in the
management of inflammatory diseases such as asthma (by the drugs montelukast and
zafirlukast), psoriasis, and rheumatoid arthritis.
The slow reacting substance of anaphylaxis comprises the cysteinyl leukotrienes.
These have a clear role in pathophysiological conditions such as asthma, allergic
rhinitis and other nasal allergies, and have been implicated in atherosclerosis and
inflammatory gastrointestinal diseases.[24] They are potent bronchoconstrictors,
increase vascular permeability in postcapillary venules, and stimulate mucus
secretion. They are released from the lung tissue of asthmatic subjects exposed to
specific allergens and play a pathophysiological role in immediate hypersensitivity
reactions.[23] Along with PGD, they function in effector cell trafficking, antigen
presentation, immune cell activation, matrix deposition, and fibrosis.[25]
[edit] History
In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib
characterized prostaglandin as a component of semen. Between 1929 and 1932, Burr
and Burr showed that restricting fat from animal's diets led to a deficiency disease,
and first described the essential fatty acids.[26] In 1935, von Euler identified
prostaglandin. In 1964, Bergström and Samuelsson linked these observations when
they showed that the "classical" eicosanoids were derived from arachidonic acid,
which had earlier been considered to be one of the essential fatty acids.[27] In 1971,
Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[28] Von
Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and
Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely
for his synthesis of prostaglandins.
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